The clinical use of the steroidal aromatase inhibitor Formestane (4-hydroxandrostenedione, 4-OHA) in the treatment of advanced ER+ breast cancer has been discontinued, and therefore, interest in this remarkable drug has vanished. As a C-19 sterol, 4-OHA can undergo extensive intracellular metabolism depending on the expression of specific enzymes in the corresponding cells. We used the metabolites 4β-hydroxyandrosterone, 4β-hydroxyepiandrosterone and its 17β-reduced derivative as standards for the proof of catalytic activity present in the cell culture medium and expressed by the isolated enzymes. All of the aldo-keto reductases AKR1C1, AKR1C2, AKR1C3 and AKR1C4 catalysed the reduction of the 3-keto-group and the Δ4,5 double bond of 4-OHA at the same time. Molecular docking experiments using microscale thermophoresis and the examination of the kinetic behaviour of the isolated enzymes with the substrate 4-OHA proved that AKR1C3 had the highest affinity for the substrate, whereas AKR1C1 was the most efficient enzyme. Both enzymes (AKR1C1and AKR1C3) are highly expressed in adipose tissue and lungs, exhibiting 3β-HSD activity. The possibility that 4-OHA generates biologically active derivatives such as the androgen 4-hydroxytestosterone or some 17β-hydroxy derivatives of the 5α-reduced metabolites may reawaken interest in Formestane, provided that a suitable method of administration can be developed, avoiding oral or intramuscular depot-injection administration.

中文翻译：

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人3α-羟基类固醇脱氢酶同工型（AKR1C1-AKR1C3）在类固醇芳香化酶灭活剂Formestane的肝外代谢中的作用。

甾体芳香酶抑制剂福尔坦斯坦（4-羟氧杂戊二酮，4-OHA）在治疗晚期ER +乳腺癌中的临床应用已中止，因此，对这种显着药物的兴趣已消失。作为C-19固醇，4-OHA可以进行大量的细胞内代谢，具体取决于特定酶在相应细胞中的表达。我们使用代谢物4β-羟基雄甾酮，4β-羟基表雄酮及其17β还原衍生物作为标准，以证明存在于细胞培养基中并由分离的酶表达的催化活性。所有的醛基酮还原酶AKR1C1，AKR1C2，AKR1C3和AKR1C4均同时催化4-OHA的3-酮基和Δ4,5双键的还原。使用微尺度热泳的分子对接实验以及对带有底物4-OHA的分离酶的动力学行为的研究证明，AKR1C3对底物具有最高的亲和力，而AKR1C1是最有效的酶。两种酶（AKR1C1和AKR1C3）都在脂肪组织和肺中高表达，表现出3β-HSD活性。4-OHA产生生物活性衍生物的可能性，例如雄激素4-羟基睾丸激素或5α还原的代谢物的一些17β-羟基衍生物，可能会重新引起对福尔马斯坦的兴趣，条件是可以开发出合适的给药方法，避免口服或肌内注射库注射管理。而AKR1C1是最有效的酶。两种酶（AKR1C1和AKR1C3）都在脂肪组织和肺中高表达，表现出3β-HSD活性。4-OHA产生生物活性衍生物的可能性，例如雄激素4-羟基睾丸激素或5α还原的代谢物的一些17β-羟基衍生物，可能会重新引起对福马斯坦的兴趣，但前提是可以开发一种合适的给药方法，避免口服或肌肉注射库注射管理。而AKR1C1是最有效的酶。两种酶（AKR1C1和AKR1C3）都在脂肪组织和肺中高表达，表现出3β-HSD活性。4-OHA产生生物活性衍生物的可能性，例如雄激素4-羟基睾丸激素或5α还原的代谢物的一些17β-羟基衍生物，可能会重新引起对福尔马斯坦的兴趣，条件是可以开发出合适的给药方法，避免口服或肌内注射库注射管理。